Relaxin: A Novel HRT for Prevention of Cardiac Disease

描述（由申请人提供）：心血管疾病是美国女性的头号杀手。与男性相比，绝经前女性冠状动脉疾病的发病率较低；然而;绝经后的风险与男性相同。雌激素替代疗法在缓解更年期症状方面是有效的，但最近的临床试验未能证明其具有显著的心脏保护作用。因此，对绝经后妇女进行“激素替代疗法”的新方法将是有用的。我们认为在月经周期的黄体期循环的卵巢激素松弛素可能有助于减少绝经前妇女冠状动脉疾病的发病率。虽然松弛素主要是作为一种生殖激素进行研究，但越来越多的证据表明，松弛素是一种有效的血管舒张剂和动脉顺应性调节剂，这可能有利于维持冠状动脉的健康。我们最近发现松弛素是一种源自血管的局部作用的松弛和顺应因子。松弛素通过减少动脉收缩和降低动脉“僵硬”来促进动脉健康。因此，我们进一步提出，血管源性松弛素或其受体的缺乏导致女性心血管疾病发病率随年龄增长而增加。在假设1中，我们将检验松弛素是否能逆转绝经后大鼠（卵巢切除的Sprague-Dawley大鼠和老年雌性SHR，我们的绝经动物模型）的冠状动脉功能障碍。我们的初步数据令人兴奋，因为它们支持我们的假设。我们还将确定舒张素对冠状动脉功能有益或促进健康作用的机制。在假设2中，我们将检验血管源性松弛素或其受体的减少是否导致冠状动脉血管功能障碍。总之，绝经前妇女冠状动脉疾病的发病率较低，这可能是由于女性激素的保护作用。在月经周期中循环的卵巢来源的松弛素或血管来源的激素可能在绝经前提供心血管保护。因此，松弛素可以作为绝经后的“激素替代疗法”。

DESCRIPTION (provided by applicant): Cardiovascular disease is the number one killer of American women. Premenopausal women have a lower incidence of coronary artery disease relative to men; however; after menopause the risk is equal to that of men. Estrogen replacement therapy is effective in relieving the symptoms of menopause but recent clinical trials have failed to demonstrate a significant cardioprotective effect. Therefore, fresh approaches to the concept of "hormone replacement therapy" in postmenopausal women would be useful. We suggest that the ovarian hormone relaxin which circulates during the luteal phase of the menstrual cycle may contribute to the reduced incidence of coronary artery disease in premenopausal women. Although relaxin has been primarily studied as a reproductive hormone, there is growing evidence that relaxin is a potent vasodilator and modifier of arterial compliance which would may make it beneficial for the maintaining coronary artery health. We have recently discovered that relaxin is a vascular derived, locally acting relaxing and compliance factor. Relaxin promotes the health of arteries by making them less contractile and decreasing arterial 'stiffness'. Therefore, we further propose that deficiency of vascular-derived relaxin or its receptor contributes to the increased incidence of cardiovascular disease with aging in women. In hypothesis 1, we will test whether relaxin reverses coronary arterial dysfunction in the post-menopausal rats (ovariectomized Sprague-Dawley rats and aged female SHR, our animal models of menopause). Our preliminary data are exciting, because they support the hypothesis. We will also determine the mechanisms underlying the salutary or health promoting effect of relaxin on coronary artery function. In hypothesis 2, we will test whether reductions in vascular-derived relaxin or its receptor contribute to coronary vascular dysfunction. In summary, premenopausal women have a lower incidence of coronary artery disease that is likely due to the protective effects of female hormones. Ovarian-derived relaxin that circulates during the menstrual cycle or vascular-derived hormone may provide cardiovascular protection prior to menopause. Therefore, relaxin may serve as a "hormone replacement therapy" after menopause. PUBLIC HEALTH RELEVANCE: This proposal outlines studies utilizing isolated rat hearts, isolated coronary arteries, and molecular biology techniques to evaluate the therapeutic potential of relaxin (Rlx) in the treatment of post menopausal coronary artery dysfunction. In addition, we will evaluate the potential contribution of vascular-derived Rlx or its receptor to this coronary artery dysfunction. Two animal models ovariectomized female rats and the aged SHR, will be used to address the aims. Our hope is that these studies may lead to the use of Rlx as an alternative HRT for human coronary artery disease.